Age-related macular degeneration (AMD; OMIM 603075), a progressive neurodegenerative disease, is the most common cause of blindness in the elderly population of developed countries (Swaroop et al. Annu Rev Genomics Hum Genet 10, (in press) (2009), Congdon et al. Arch Opthalmol 122, 477-85 (2004), herein incorporated by reference in their entireties). The disease affects primarily the macular region of the retina, which is necessary for sharp central vision. An early hallmark of AMD is the appearance of drusen, which are extracellular deposits of proteins and lipids under the retinal pigment epithelium (RPE). As the disease progresses, the drusen grow in size and number. In advanced stages of AMD, atrophy of the RPE (geographic atrophy) and/or development of new blood vessels (neovascularization) result in central vision loss due to the death of photoreceptors (Swaroop et al. Annu Rev Genomics Hum Genet 10, (in press) (2009), Jager, et al. N Engl J Med 358, 2606-17 (2008), Jackson et al. Ageing Res Rev 1, 381-96 (2002), herein incorporated by reference in their entireties).
In recent years, progress has been made in identifying genetic contributors to AMD susceptibility. A series of genetic linkage scans provided strong evidence for multiple susceptibility loci, notably on chromosomes 1q31 and 10q26 (Fisher et al. Hum Mol Genet 14, 2257-64 (2005), herein incorporated by reference in its entirety). Disease associated variants near complement factor H (CFH, 1q32) and a gene of poorly understood function (ARMS2, 10q26) were soon identified at these two loci through a combination of genomewide association scans (Klein et al. Science 308, 385-9 (2005), Dewan et al. Science 314, 989-92 (2006), herein incorporated by reference in their entireties) and fine-mapping of linkage signals (Rivera et al. Hum Mol Genet 14, 3227-36 (2005), Jakobsdottir et al. Am J Hum Genet 77, 389-407 (2005), Haines, et al. Science 308, 419-21 (2005), Edwards et al. Science 308, 421-4 (2005), herein incorporated by reference in their entireties). Discovery of association between AMD and the CFH locus was particularly transforming, leading to the identification of additional susceptibility loci including C2/CFB, C3, and CFI (Fagerness et al. Eur J Hum Genet 17, 100-4 (2009), Gold et al. Nat Genet 38, 458-62 (2006), Maller et al. Nat Genet 39, 1200-1 (2007), Yates et al. N Engl J Med 357, 553-61 (2007).), herein incorporated by reference in their entireties).